Process for preparing 4-{8 3-(substituted amino)-2-hydroxypropoxy{9 -1,2,5-thiadiazoles

ABSTRACT

Preparation of S-3-X-4-(3-substituted amino-2-hydroxypropoxyl)1,2,5-thiadiazole Beta -adrenergic blocking agents using as starting material an optically active oxazolidine in the sinister configuration which is reacted with a 3-X-4-RO-1,2,5thiadiazole.

United States Patent [191 Weinstock et al.

[73] Assignee: Merck & Co., Inc., Rahway, NJ.

[22] Filed: Dec. 18, 1973 [21] Appl. No.: 425,912

Related US. Application Data [60] Continuation-impart of Ser. No. 284,0]3, Aug. 25, 1972, abandoned, which is a division of Ser. No. 172,234, Aug. 16, 1971, Pat. No. 3,718,647, which is a division of Ser. No, 818,474, April 2|, 1969, Pat. No. 3,657,237.

[52] US. Cl ..260/247.1 H; 260/268 H; 260/293.68; 260/308 D [451 July 1,1975

[51] Int. Cl. C07D 295/12; C07D 285/10 [58] Field of Search..... 260/247.1 H, 302 D, 268 H, 260/293.68

[56] References Cited UNITED STATES PATENTS 3,657,237 4/1972 Weinstock et al. 260/2471 H Primary ExaminerLorraine A. Weinberger Assistant ExaminerMichael Shippen Attorney, Agent, or Firm-Daniel T. Szura; J. Jerome Behan [57] ABSTRACT Preparation of S-3-X-4-( 3-substituted amino-2- hydroxypropoxyl )-l ,2,5-thiadiazole ,B-adrenergic blocking agents using as starting material an optically active oxazolidine in the sinister configuration which is reacted with a 3-X-4-RO-1,2,5-thiadiazole.

6 Claims, No Drawings 1 2 PROCESS FOR PREPARING 4-[3-(SUBSTITUTED alkyl (C =;)-l-piperazinyl; and Y is a straight or AMINO)-2-HYDROXYPROPOXY]-1,2,5- branched chain lower alkyl having from 1 to 5 carbon THIADIAZOLES atoms which is optionally hydroxy substituted.

This application is a continuation-in-part of copend- When in the foregoing reaction scheme R in the thiaing Application Ser. No, 284,013 now abandoned, filed 5 diazole I is chloro then the, R-alkamine is an (S)- Aug. 25, 1972 which was a division of Appication Ser. oxazolidine of the structure No. 172,234, filed Aug. 16, 1971, now US. Pat. No.

3,718,647, issue date Feb. 27, 1973, which, in turn was HOCH2-CH CH2 a division of Application Ser. No. 818,474, filed Apr. I 21, 1969, now US. Pat. No. 3,657,237, issue date Apr. 0 18, 1972.

This invention is concerned with a novel and commercially feasible method for preparing the biologically Z active, S-enantiomer of a 3-X-4-(3-substituted amino- Application -hydroxypropoxy)-l ,2,5thiadiazole prodor an alkali metal salt thereof as specified above, uct. Substantially all of the biological activity of these wherein Y has the meaning assigned above and Z is the products resides in the S-enantiomer which was obresidue of any known aldehyde; any one of which can tained by other workers by the resolution of the racebe employed in the synthesis of the oxazolidine. mic product or by the resolution of intermediates em- When R in the thiadiazole reactant l is hydroxy, then ployed in their synthesis. These prior methods offer the hydroxyl group of the R-alkamine is activated by several disadvantages, principally the need to use cyforming a leaving group, i.e., an easily displaceable anogen for the synthesis of the intermediate 3-chlorogroup, such as a sulfonate of the aforementioned ox- 4-hydroxy-l,2,5-thiadiazole, an important intermediazolidines. ate, as well as the need to resolve the 3-X-4-(3- When R in compound I is chloro and Rin compound substituted amino-2-hydroxypropoxy)-l,2,5- 11 represents the reactive hydroxyl group, the optically thiadiazole derivative thereof. It is well known that resactive product, S-Ill, is prepared by the reaction of the olution procedures are uneconomical as they provide thiadiazole I and the S-alkamine, S-II, in the presence low yields of active material because half of the yield of a strong base. The reaction preferably is carried out of racemic product formed is of no value, and at least at ambient temperature although the reaction mixture some of the desired isomer is not recoverable by feasieither can be heated up to reflux temperature if deble large scale procedures. sired, or cooled to 0C. A solvent for the reactants is This invention therefore is concerned principally desirable and any conventional solvent can be emwith the preparation of optically active 3-X-4-(3- ployed for this purpose; suitable ones being polar substituted amino-2-hydroxypropoxy)-l,2,5- aprotic solvents such as 'dimethylformamide (DMF),

thiadiazoles utilizing in the synthesis thereof derivatives dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), of optically active carbohydrates thus avoiding all of hexamethylphosphoramide (HMP), lower alkanols and the difficulties encountered by other workers in the res the like. The readily available and relatively inexpenolution of the end product itself or the need to resolve sive tert-butanol has been found to be a quite suitable, racemic compounds at any stage of the synthesis of the general purpose solvent for these intermediates. Strong active end products, or the need to employ cyanogen bases that are recommended for use in the reaction are in the syntheses of the thiadiazole starting material. alkali metal alkoxides or alkali metal hydroxides pref- According to the principal process of this invention erably the sodium or potassium alkoxides or hydroxa 1,2,5-thiadiazole, structure I, is reacted with an optiides, or sodium hydride. Itis unnecessary to employ a strong base if the alkali metal salt of the hydroxyalkacally active alkamine of the sinister (S) configuration,

mine is preformed. When product S-III in the form of structure I], to provide product 111 in the sinister configuration. Either structure I compound or structure 11 the free base is obtained as an oil, crystalline material compound contains a reactive hydroxyl group or an 211- can be prepared by forming the salt by known methods. kali metal salt thereof, thus the reaction can be illus- Suitable salts are those formed with mineral acids or trated by the following scheme: organic acids such as, for example, the hydrochloride (DH Xl "-R X'-'"O-CH2CHCH2NHY 1 N R alk mlne N N a I S-II S-III wherein either R or R is the reactive hydroxyl group salt, the sulfate salt, the hydrogen maleate salt or other or an alkali metal salt thereof wherein the alkali metal desired mineral or organic acid salt preferably is sodium or potassium. When R is HO- or When R in compound I represents the reactive hy- (alkali metabofi then R s hl r when R is 01-] or a droxyl group or the alkali metal salt thereof and R is salt thereof, then R is the sulfonate derivative of the an activated hydroxyl group, the reagents are coupled alkamine. X in the above structures represents chloro, advantageously b bi i h reactants i h lower alkyl having 1 to 3 carbon atoms, lower alkoxy ner described above, that is, in the presence of a strong havin f om 1 to 3 carbon atoms, phenyl, benzyl, morbase and a solvent to form the desired product, S-III. phOlinO, piperidin0. hy r xypip i and N-lowef The strong base and the solvent to be employed are those identified above. If the alkali metal salt of the hydroxythiadiazole is preformed, it is not necessary to add the strong base to the reaction mixture. Heating the reaction mixture up to the reflux temperature can be employed if desired and any of the usual organic solvents can be used, especially suitable ones being polar aprotic solvents, such as DMF, DMSO, THF, HMP, lower C alkanols and the like.

The novel process of this invention is particularly concerned with the preparation of an optically active thiadiazole in the sinister configuration having structure S-III:

by the reaction of a compound having structure I with a compound having structure S-ll:

in the presence of'a strong base selected from an alkali metal alkoxide, alkali metal hydroxide or sodium hydride followed by acid hydrolysis. If desired, the sodium salt of reactant I can be preformed in which event a strong base need not be added to the reaction mixture. In the foregoing structures, X and Y have the meaning hereinbefore assigned, Z is the residue of any known aldehyde having the structure ZCHO advantageously an aliphatic, alicyclic, aromatic or heterocyclic residue of an aldehyde of structure ZCHO, and R is a sulfonyl group advantageously an alkylsulfonyl, arylsu'lfonyl or aralkylsulfonyl. I

The R -alkamines of the sinister configuration, S-ll, can be prepared by a novel method that constitutes another feature of this invention.

The S-oxazolidines are prepared by the reaction of- S-l,2-dihydroxy-3-amino(or substituted amino)propane or the S-lsulfonyloxy-2-hydroxy-3-amino(or substituted amino)-propane with any aldehyde, ZCHO, to provide an S-oxazolidine of the structure:

the cyclic structure which subsequently is cleaved by hydrolysis to remove the grouping provided by the aldehyde. For practical purposes any commercially available and inexpensive aldehyde can be employed and among these there can be mentioned aliphatic aldehydes, alicyclic, aromatic or heterocyclic aldehydes such as lower alkyl aldehydes, benzaldehyde, phenyl-lower alkyl aldehydes, and the like, the phenyl moiety of either of the latter aldehydes optionally having one or more similar or dissimilar substituents selected from halogen, lower alkyl, halo alkyl, amino, acylamino, monoor di-alkylamino, nitro, alkoxy, phenalkoxy, haloalkoxy and hydroxy, a heterocyclic aldehyde optionally having substituents as halogen, lower alkyl, phenalkyl and the like. Among the many aldehydes that can be employed there can be mentioned acetaldehyde, propionaldehyde, butyraldehyde, phenylacetaldehyde, anisaldehyde, benzaldehyde, mesitaldehyde, tolualdehyde, furfural and the like. As mentioned above, R can be hydrogen or an alkyl-,

R O-CIE-m arylor aralkylsulfonate. The sulfonate is prepared by reaction of the hydroxymethyloxazolidine with any known and particularly any commercially available sulfonyl halide. As any sulfonyl halide will activate the hydroxyl group and as the sulfonyl moiety is subsequently removed, it is not critical that any particular sulfonyl halide be employed to form the sulfonyloxy derivative of the S-l,2-dihydroxy-3-amino(or substituted amino)- propane. For practical purposes, commercially available I and inexpensive sulfonyl halides would be employed for this purpose and these would fall into the class of alkylsulfonyl halides and benzenesulfonyl halides wherein the benzene moiety can optionally be substituted with one or more similar or dissimilar substituents selected from lower alkyl, lower alkoxy, halo, amino and nitro substituents. Among the commercially available sulfonyl halides that can be employed for this purpose there can be mentioned methanesulfonyl chloricle, benzenesulfonyl chloride, nitrobenzenesulfonyl "chloride, bromobenzenesulfonyl chloride, chloroben- 'zenesulfonyl chloride, toluenesulfonyl chloride, toluenesulfonyl fluoride, trichlorobenzenesulfonyl chloride, tribromobenzenesulfonyl chloride, fluorobenzenesulfonyl chloride, 4-chloro-2(or 3 nitrobenzenesulfonyl chloride, hexadecanesulfonyl chloride, Z-mesitylenesulfonyl chloride, methoxybenzenesulfonyl chloride and the like.

The S-l,2-dihydroxy-3-amino(or substituted amino)- propane employed as starting substance can be made in. a single step and in quite good yield by the reductive alkylation of the selected amine with glyceraldehyde. The success of this process was not predictable from the prior art that teaches that glyceraldehyde cyclizes in the presence of base. It was found; however, that reductive alkylation can be effected by hydrogenating a mixture of the selected amine, glyceraldehyde and a hydrogenation catalyst. Hydrogenation advantageously is carried out under a pressure from about 1 to about atmospheres. Any solvent can be employed, suitable ones being tetrahydrofuran, methanol, a mixture of benzene and methanol and the like. Suitable catalysts are platinum, Raney nickel and palladium. While for the present invention one employes an amine of the structure YNH and D-glyceraldehyde, it will be appreciated that any amine such as ammonia, a primary or secondary amine, or a nitrogen-containing heterocycle of the structure can be reductively alkylated with glyceraldehyde by the novel method of this invention.

The 8-1 ,2-dihydroxy-3-amino(or substituted amino)- propane having an activated hydroxyl group is prepared by reaction with any known and particularly any commercially available sulfonyl halide such as those identified above. The 1-sulfonyloxy-2-hydroxy-3- amino(or substituted amino)-propane thus formed can itself be reacted with an aldehyde of formula ZCHO by the procedure described above to provide the desired 2-Z-3-Y-5-R OCH -oxazo1idine of structure 8-".

Preparation of S-3-X-4-[3-(Y-amin0)-2-hydroxypropoxy]-1 ,2,5- thiadiazole via 3-X-4-chloro- 1 ,2,5-thiadiazole EXAMPLE 1 Step A: Preparation of S()-glyco1amine A mixture of tert-butylamine (37.44 g.; 0.513 mole), methanol (150 ml.) and 5% pa11adium-on-carbon (1.0 g.) is shaken in a hydrogenation bomb under these atmospheres hydrogen pressure. A solution of D- glyceraldehyde (15 g.) in methanol (60 ml.) is added over a one hour period during hydrogenation. After the addition, the mixture is shaken for an additional 15 hours. The catalyst is removed by filtration and the solvent evaporated in vacuo yielding (S(-)-)- 1,2- dihydroxy-3-tert-buty1aminopropane [S(-)- glycolamine] in the form of an oil which is crystallized by trituration with ether to give 1 1.0 g. (45%) yield of product, m.p. 8082C. [och-30.1 (1N aqueous HCl).

Step B: Preparation of S-3-tert-buty1-5-hydroxymethyloxazolidine A mixture of S()-glycolamine (29.4 g.; 0.2 mole), aqueous formaldehyde ml. of 37% solution) and benzene (80 ml.) is heated under reflux with continuous removal of water for two hours. The solvent then is evaporated in vacuo (15 mm. pressure) and the oily residue distilled, b.p. 8082C., (0.5 mm. pressure) providing 29.9 g. (94%) S-3-tert-butyl-5-hydroxymethyloxazolidine.

Step C: Preparation of 3-morpholino-4-chloro-1,2,5thiadiazole 3,4-Dichloro-1,2,5-tl1iadiazo1e (100.0 g.; 0.645 mole) is added dropwise over a 30-minute period at l05-1 10C. to morpho1ine(224 ml.; 2.58 mole). After the addition,

centrated hydrochloric acid (250 ml.) whereupon an insoluble oil soon crystallizes to a heavy solid mass. After crystallization is complete the solid is filtered and washed with water and then dried at 35C. in vacuo yielding 125.5 g. of 3morpho1ino-4-ch1oro- 1,2,5-thiadiazole, m.p. 4345C.

Step D: Preparation of S ()-3 -morpholino-4-( 3-tert-butyl amino-2-hydroxypropoxy)-1,2,5-thiadiazole and its hydrogen maleate salt A mixture of 3-morpho1ino-4-ch1oro-1,2,5- thiadiazole (2.05 g.; l0mmole), S-3-tert-butyl-5- hydroxymethyloxazolidine (l0mmole) and potassium tert-butoxide in tert-butanol (1 1.7 ml. of 0.885N, 10mmo1e) is stirred at 25C. for 16 hours. The solvent then is evaporated in vacuo and the residue treated with 20 ml. of 1N hydrochloric acid. The mixture is heated at 65C. for one-half hour, cooled to 25C. and extracted with ether. The aqueous layer is made alkaline with potassium carbonate and extracted with ether. The extracts are washed with water, dried and evaporated to an oily residue of S(-)-3-morpholino-4-(3-tertbutylamino-2-hydroxypropoxy)-1 ,2,5-thiadiazole. This oil in 50 ml. of tetrahydrofuran is treated with charcoal (1.5 g.), filtered, and the cake washed with 20 ml. of tetrahydrofuran. To this solution is added maleic acid; 1 mole equivalent per mole of S()-3-morpholino-4- (3-tert-butylamino-Z-hydroxypropoxy)-1,2,5-' thiadiazole dissolved in tetrahydrofuran (25 ml.). The mixture then is seeded and aged 1 hour at 25C. The crystallized hydrogen maleate salt is separated by fi1tra tion, washed with tetrahydrofuran and dried at 50C. in vacuo to give a 30% yield of S-(-)-3-morpholino-4-(3- tert-butylamino-2-hydroxypropoxy)-1,2,5-thiadia2ole hydrogen maleate.

Byreplacing the maleic acid employed in the above procedure by hydrochloric acid, sulfuric acid, tartaric acid or any other desired acid the corresponding acid salt is formed. When sulfuric acid is employed in the ratio of 1 mole of acid to 2 moles of thiadiazole, the sulfate salt of S(-)-3-morpholino-4-(3-tert-butylamino-2- hydroxypropoxy)-l,2,5-thiadiazole is obtained, m.p. 253.5254C. [04], 13.8 [C =1,'1N HCl By replacing morpholine in Step C with an equivalent quantity of N-methylpiperazine, piperidine and 4- hydroxypiperidine and then following substantially the same methods of Steps C and D, there is obtained, respectively, the 3-(4-methylpiperazinyl)-, 3-piperidy1-, and 3-(4-hydroxypiperidiyl)- analogs.

By replacing the tert-butylamine employed in Step A by an equivalent quantity of isopropylamine, 2,2- dimethylpropylamine, and 1 ,1 -dimethy1-2- hydroxyethylamine and following substantially the same procedures described in Steps A-D there is ob tained S-()-3-morpho1ino-4-[3-(Y-amino)-2- hydroxypropoxy]-1,2,5-thiadiazole hydrogen maleate compounds wherein Y is isopropyl, 2,2- dimethylpropyl, and 1,1-dimethyl-2-hydroxyethyl, respectively.

EXAMPLE 2 Step A: Preparation of S=2'-isopropy1-3-tert-buty1-5-hydroxymethy1oxazolidine the mixture is stirred 2 hours at 1O5-1 10C., then cooled to 15C. and quenched with, water (250 m1.). This mixture is made acidic with con- A mixture of S()-glycolamine g.; 68 mmole) in freshly distilled isobutyraldehyde (50 ml.) is heated under reflux with continuous removal of water'for 2 hours. The solvent then is removed in vacuo and the oily residue distilled. A forerun of 0.85 g. of material with b.p. 7075C. (0.1 mm. pressure) is obtained which is 98% pure S-2-isopropyl-3-tert-butyl-5-hydroxymethyloxazolidine when analyzed by vapor pressure chromatography(vpc).

Step B: Preparation of S(-)-3-morpholino-4-( 3-tert-butylamino-Z-hydroxypropoxy)-1,2,5-thiadiazole and its hydrogen maleate salt This product is obtained in 35 percent yield by following the procedure described in Example 1, Step D, with the exception that 10 mmole of S-2-isopropyl-3- tert-butyl-5-hydroxymethyloxazolidine is substituted for the oxazolidine employed in Example 1, Step D.

EXAMPLE 3 Step A: Preparation of S-2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidine A mixture of S()-glycolamine (20 g.; 0.136 mole), benzaldehyde (50 ml.; 288mmole) and benzene (30 ml.) is heated under reflux for 8 hours while removing the water as formed into a Dean Stark trap filled with benzene. The temperature of the reaction mixture is maintained at llOl 13C. over the entire period. The benzene is removed in vacuo (15 mm. pressure) and the excess benzaldehyde is removed by distillation at 0.1 mm. pressure. The residual oil (31.9 g.; 99% yield) is 90% pure S-2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidine by vpc and can be used directly in the next step. If desired, the oxazolidine can be distilled (105108C.; 0.002 mm. pressure) to provide 96% pure product.

Step B: Preparation of S( -)-3-morpholino-4-( 3-tert-butylamino-2-hydroxy propoxy)-l,2,5-thiadiazole and its hydrogen maleate salt The above product is prepared in 50% yield by the process described in Example I, Step D, except l0 mmole of S-2-phenyl-3-tert-butyl-5-hydroxymethyloxazolidine is substituted for the oxazolidine employed in Example 1, Step D. k

Any other aldehyde, particularly (though not necessarily) any of the commercially available aldehydes identified hereinabove can be reacted with an S-l,2- dihydroxy-3-amino(or substituted amino)propane or an S-l-sulfonyloxy-2-hydroxy3-amino(or substituted amino)propane by the method illustrated in Step B of Example 1 or Step A of Examples 2 or 3, to provide the desired S-oxazolidine which then can be reacted with the appropriate 1,2,5-thiadiazole by the procedure of Example 1, Step D or Example 4, Step B, to give product S-Ill, substantially completely free from contamination with the rectus isomer.

EXAMPLE 4 Step A: Preparation of S-3-tert-butyl-5-( benzenesulfonyloxymethyl )oxazolidine To a solution of S-3-tert-butyl-5-hydroxymethyloxazolidine 1.59 g.; 10 mmole), prepared as described in Example 1, Step B, in pyridine (3 ml.) there is added benzenesulfonyl chloride (10 mmole) and the mixture stirred for about 1 hour at 25C. Ether (20 ml.) is added whereupon S-3-tert-butyl-5- (benzenesulfonyloxymethyl )oxazolidine hydrochloride is precipitated, removed by filtrationand washed well with ether and dried in vacuo at 40C.

The same oxazolidine product is obtained by replacthe S(.-)-glycolamine employed in Example .1, Step B, by an equivalent quantity of S-l-benzenesulfonyloxy-2- hydroxy-3-tert-butylaminopropane and then following substantially the same procedure described in Step B of Example 1.

By replacing the benzenesulfonyl chloride employed in Step A by 10 mmole of p-tolylsulfonyl chloride, pnitrobenzenesulfonyl chloride, and pbromobenzenesulfonyl chloride there is obtained respectively:

S-3-tertbutyl -5-(p-toluenesulfonyloxymethyl)oxazolidine, m.p. l43.5l45C., yield 83.5%;

'S-3-tert-butyl- 5-(p-nitrobenzenesulfonyloxymethyl)- oxazolidine, yield 98%,

S-3-tert-butyl-5-(p-bromobenzenesulfonyloxymethyl)-oxa zolidine, m 11s-120c., yield By replacing the benzenesulfonyl chloride by an equivalent quantity of methanesulfonyl chloride and/or other lower alkylsulfonyl chloride, p-chlorophenyls'ulfonyl chloride, or any other sulfonyl halide, particularly (though not necessarily) any of the commercially available sulfonylhalides identified hereinabove in the process illustrated in Step A of this example for reaction with any desired S-5-hydroxymethyloxazolidine provides the sulfonyloxy derivatives thereof which upon reaction with the appropriate 1,2,5-thiadiazole according to Step B of this example gives product S-Ill.

Step B: Preparation of S()-3-morpholino-4-(3-tert-butylamino-2-hydroxypropoxy)-l,2,5 thiadiazole hydrogen maleate S-3-tert-butyl-5-(benzenesulfonyloxymethyl)oxazoli dine (1O mmole) is dissolved in benzene (12 ml.) and tetrahydrofuran (0.9 ml.). The sodium salt of 3- morpholino-4-hydroxy-l,2,5 thiadiazole (1O mmole) is added and the mixture refluxed for 16 hours.,The reaction mixture then is extracted with three 10 ml. portions of lN hydrochloric acid and the aqueous layer then made alkaline with ammonia and extracted with three 10 ml. portions of benzene. The combined benzene extracts 'are'dried and evaporated to give S()-3- morpholino-4-( 3-tert-butylamino-Z-hydroxypropoxy)- 1,2,5-thiadiazole.'This product is converted to the hydrogen maleate salt by treatment with maleic 'acid in tetrahydrofuran by substantially the same procedure described in Example 1, Step D, to providea 32% yield of S()-3-m0rpholino-4-( 3-tert-butylamino-2- hydroxypropoxy)-l ,2,5-thiadiazole hydrogen maleate.

By replacing the S-3-tert-butyl-5-- (benzenesulfonyloxymethyl)oxazolidine employed in Step B by an equimolecular quantity of:

S-3-tert-butyl-5-(p-toluenesulfonyloxymethyl)oxazolidine, I

S-3-tert-butyl-5-(p-nitrobenzenesulfonyloxymethyl) oxazolidine, and

S-3-tert-butyl-5-(p-bromobenzenesulfonyloxymethyl)-oxazolidine and followingsubstantially the same procedure described in Step B above there is obtained the free base 9 and the hydrogen maleate salt of S()-3-morpholino-4- (3-tert-butylamino-2-hydroxypropoxy)-1,2,5- thiadiazole in substantially the same yield.

By replacing the 3-morpholino-4-hydroxy-l,2,5- thiadiazole employed in Step B of Example 4 by an equivalent quantity of the following:

1. 3-chloro-4-hydroxy-1,2,5-thiadiazole or its alkali metal salt,

2. 3-ethyl-4-hydroxy-l,2,5-thiadiazole or its alkali metal salt,

3. 3-ethoxy-4-hydroxy-1,2,5-thiadiazole or its alkali metal salt,

4. 3-phenyl-4-hydroxy-1,2,5-thiadiazole or its alkali metal salt,

5. 3-benzyl-4-hydroxy-l,2,5-thiadiazole or its alkali metal salt and following substantially the same procedure described in Step B of Example 4, when the alkali metal salt form is employed, or when the free hydroxy form is used, following the procedures of Example 1, Step D, employing any one of the strong bases described above, there is obtained respectively, the S-3chloro-, S-3- ethyl-, S'3-ethoxy-, S-3-phenyl.-, and S-3-benzyl-4-(3- tert-butylamino-Z-hydroxypropoxy)-1,2,5-thiadiazole.

The S-3-X-4-[3-(Y-amino)-2-hydroxypropoxy]- 1,2,5-thiadiazole compounds prepared by the process of this invention as well as their salts have been found to exhibit B-adrenergic blocking properties and are thus useful in the management of angina pectoris. Because of this property the optically active products are useful for the control of tachycardia that may be drug induced (as by isoproterenol) or brought about by physiological conditions.

The optically active products particularly in the form of their salts can be prepared in pharmaceutical formulations suitable for oral or parenteral administration and also can be combined with other active ingredients for simultaneous administration. No special problems are involved in preparing suitable formulations of the optically active compounds or salts thereof and methods generally employed for this purpose, which are known to those skilled in this art, are entirely suitable. Dosage units of from about 2 mgs. to about mgs. can be provided for the symptomatic adjustment of dosage of the optically active substances by the physician depending upon the age and condition of the patient.

Illustrative examples of suitable pharmaceutical compositions containing S()-3-mor pholino-4-(3-tertbutylamino-l2-hydroxypropoxy)-1,2,5-thiadiazole hydrogen maleate as active ingredient follow. Each of the compositions are prepared by conventional methods, and the quantities recited are for each unit dosage. The other optically active products prepared as hereinbefore described can be similarly formulated.

lnjectable Solution Active Compound l mg.

Sodium chloride 9 mgs.

Distilled water q.s. l.0 ml.

Capsules Active Compound 5 mgs.

Magnesium stearate 2.0 mg.

Lactose U.S.P. l9.3 mg.

What is claimed is: 1. A process for the preparation of an optically active thiadiazole in the sinister configuration having the structure S-III,

S-III comprising the reaction of a compound of structure I with a compound of structure S-ll,

X 0 Alkali metal N\ /N S 3 R OCH O N-Y S-II followed by acid hydrolysis wherein the variable radical X is selected from chloro, C alkyl, C, alkoxy, phenyl, benzyl, morpholino, piperidino, hydroxypiperidino, and N-C alkyl-l-piperazinyl, Y is a straight or branched chain C alkyl; Z is hydrogen or an aliphatic, alicyclic, aromatic or heterocyclic residue of the aldehyde ZCHO used to form the oxazolidine nucleus; and R is alkylsulfonyl, arylsulfonyl or aralkylsulfonyl.

2. A process as in claim lwherein the reaction is carried out at a temperature between about 0 to reflux.

3. A process as in claim 2 wherein reactant l is the sodium salt of 3-morpholino-4-hydroxy-l,2,5-thiadiazole and reactant 8-11 is S-3-tert-butyl-5-(ptoluenesulfonyloxymethyl)-oxazolidine to provide S- ()-3-morpholino-4-(3-tert-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole.

4. A process as in claim 2 wherein reactant l is the sodium salt of 3-morpholino-4-hydroxy-l ,2,5-thiadiazole and reactant 5-11 is S-3-tert-butyl-5-(pnitrophenylsulfonyloxymethyl)-oxazolidine to provide S-()-3-morpholino-4-(3-tert-butylamino-2-hydroxypropoxy)-1 ,2,5-thiadiazole.

5. A process as in claim 2 wherein reactant l is the sodium salt of 3-morpholino-4-hydroxy-l,2,5-thiadiazole and reactant 8-11 is S-3-tert-butyl-5-(pbromobenzenesulfonyloxym-ethyl)-oxazolidine to provide S ()-3-morpholino-4-( 3-tert-butylamino-2- hydroxypropoxy)-1,2,5-thiadiazole.

6. The process as in claim 2 wherein reactant l is the sodium salt of 3-morpholino-4hydroxy-1,2.5- thiadiazole and reactant S-ll is S-3-tert-butyl-5-(benzenesulfonyloxymethyl) oxazolidine to provide S-()- 3-morpholino-4-( 3-tert-butylamino-2-hydroxypropoxy)-l ,2,5-thiadiazole. 

1. A PROCESS FOR THE PREPARATION OF AN OPTICALLY ACTIVE THIADIAZOLE IN THE SINSTER CONFIGURATION HAVING THE STRUCTURE S-III,
 2. A process as in claim 1 wherein the reaction is carried out at a temperature between about 0* to reflux.
 3. A process as in claim 2 wherein reactant I is the sodium salt of 3-morpholino-4-hydroxy-1,2,5-thiadiazole and reactant S-II is S-3-tert-butyl-5-(p-toluenesulfonyloxymethyl)-oxazolidine to provide S-(-)-3-morpholino-4-(3-tert-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole.
 4. A process as in claim 2 wherein reactant I is the sodium salt of 3-morpholino-4-hydroxy-1,2,5-thiadiazole and reactant S-II is S-3-tert-butyl-5-(p-nitrophenylsulfonyloxymethyl)-oxazolidine to provide S-(-)-3-morpholino-4-(3-tert-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole.
 5. A process as in claim 2 wherein reactant I is the sodium salt of 3-morpholino-4-hydroxy-1,2,5-thiadiazole and reactant S-II is S-3-tert-butyl-5-(p-bromobenzenesulfonyloxymethyl)-oxazolidine to provide S-(-)-3-morpholino-4-(3-tert-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole.
 6. The process as in claim 2 wherein reactant I is the sodium salt of 3-morpholino-4-hydroxy-1,2,5-thiadiazole and reactant S-II is S-3-tert-butyl-5-(benzenesulfonyloxymethyl) oxazolidine to provide S-(-)-3-morpholino-4-(3-tert-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole. 